Propofol-Lipuro 0.5 % (5 mg/ml) – patient leaflet, side effects, dosage

1. What Propofol- Lipuro 0.5 % (5 mg/ml) is and what it is used for

Propofol-Lipuro belongs to a group of medicines called general anaesthetics. General anaesthetics are used to cause unconsciousness (sleep) so that surgical operations or other procedures can be performed. They can also be used to sedate you (so that you are sleepy but not completely asleep).

Propofol is used to

• induce general anaesthesia in adults and children > 1 month
• sedate adult patients > 16 years of age during diagnostic and surgical procedures for a short time, alone or in combination with local or regional anaesthesia
• induce sedation in adults and children > 1 month during diagnostic and surgical procedures,.

2. What you need to know before you use Propofol-Lipuro 0.5 % (5 mg/ml)

Do not use Propofol-Lipuro 0.5 % (5 mg/ml)

• if you are allergic (hypersensitive) to propofol, soya, peanut or any of the other in-gredients of this medicine (listed in section 6).
• for maintenance of general anaesthesia or of sedation for diagnostic and surgical procedures in children
• for sedation during intensive care.

Warnings and precautions

Talk to your doctor or pharmacist before receiving Propofol-Lipuro 0.5 % (5 mg/ml). Special care has to be taken

• if you have serious head injuries,
• if you have a mitochondrial disease,
• if you have a disorder in which your body does not handle fat properly,
• if you have any other health problems which require much caution in the use of fat emulsions,
• if your blood volume is too low (hypovolaemia),
• if you are very weak (debilitated) or have heart, kidney or liver problems,
• if you have high pressure within in the skull,
• if you have problems with your breathing,
• if you have epilepsy,
• if you are undergoing some procedures where spontaneous movements are particu-larly undesirable.

Please tell your doctor if you have one of these diseases or conditions. If you are receiving other lipids by a drip into your vein at the same time your doctor will pay attention to your total daily fat intake.

Propofol will be administered to you by a physician trained in anaesthesia or intensive care. You will be constantly monitored during anaesthesia and waking-up time. If you experience signs of the so called ‘propofol infusion syndrome’ (for a detailed list of the symptoms see section 4 ‘Possible side effects’, a doctor must be called if the fol-lowing happen’) your doctor will immediately stop the dosage of propofol. Please see also section ‘Driving and using machines’ for precautions to be taken after the use of propofol.

Children and adolescents

The use of Propofol-Lipuro 0.5 % (5 mg/ml) is not recommended in newborn infants Other medicines and Propofol-Lipuro 0.5 % (5 mg/ml)

Tell your doctor or pharmacist if you are taking or have recently taken or might take any other medicines.

Propofol has effectively been used with different regional anaesthesia techniques that only numb a part of your body (epidural and spinal anaesthesia).

Additionally, safe use has been demonstrated in combination with

• drugs you receive before surgery

• other medicines like muscle relaxing drugs

  • anaesthetic drugs that can be inhaled
  • pain killers.

However your physician may give you lower doses of propofol if general anaesthesia or sedation is needed as a supplement to regional anaesthesia techniques. Special care will also be taken if you receive in parallel an antibiotic containing ri-fampicin – you may develop profound low blood pressure.

Propofol-Lipuro 0.5 % (5 mg/ml) and alcohol

Your doctor will advise you on the consumption of alcohol before and after the use of Propofol-Lipuro.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. Propofol-Lipuro 0.5 % (5 mg/ml) should not be used during pregnancy unless it is definitely needed. It crosses the placenta and may depress the vital functions of the newborn.

However, propofol may be used during an induced abortion.

If you are breast-feeding your child you should stop nursing and discard breast milk for 24 hours after you have received Propofol-Lipuro 0.5 % (5 mg/ml). Studies in breast-feeding women showed that propofol is excreted in small amounts into the milk. Driving and using machines

You should not drive or operate machinery for a while after you have an injection or infusion of Propofol-Lipuro.

Your doctor will advise you

• if you should be accompanied when you are leaving.
• when you can drive and use machinery again.
• on the use of other tranquillizing drugs (e.g. tranquillizers, strong pain killers, al-cohol).

Propofol-Lipuro 0.5 % (5 mg/ml) contains sodium and soya-bean oil

This medicine contains less than 1 mmol sodium (23 mg) in 20 ml, that is to say es-sentially ‘sodium free’.

Propofol-Lipuro 0.5 % (5 mg/ml) contains soya oil. If you are allergic to peanut or soya, do not use this medicinal product.

3. How to use Propofol-Lipuro 0.5 % (5 mg/ml)

Propofol-Lipuro 0.5 % (5 mg/ml) will only be given by anaesthetists or by specially trained doctors in an intensive care unit.

Dosage

The dose you are given will vary depending on your age, body weight and physical condition. The doctor will give the correct dose to start anaesthesia or to achieve the required level of sedation, by carefully watching your responses and vital signs (pulse, blood pressure, breathing, etc). The doctor will also observe the limits of the time of application, if necessary.

Propofol-Lipuro 0.5 % (5 mg/ml) will usually be given by injection when used to induce general anaesthesia. When used as a sedative it will usually be administered slowly and continuously by infusion using an appropriate apparatus. When given as an infusion it will be diluted in advance.

Propofol-Lipuro 0.5 % (5 mg/ml) will only be given for a maximum of 1 hour. PACKAGE LEAFLET: INFORMATION FOR THE USER Propofol-Lipuro 0.5 % (5 mg/ml) emulsion for injection or infusion

Propofol

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.

• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.See section 4.

  B.Braun Melsungen AG

  34209 Melsungen

  Germany

  B|BRAUN

Propofol should not be given to pregnant woman except when absolutely necessary. Propofol crosses the placenta and can cause neonatal depression. Propofol can how-ever be used during induced abortion.

Breast-feeding

Studies of breast-feeding mothers showed that small quantities of propofol are ex-creted in human milk. Women should therefore not breastfeed for 24 hours after ad-ministration of propofol. Milk produced during this period should be discarded. 4.7 Effects on ability to drive and use machines

Patients should be advised that performance at skilled tasks, such as driving and oper-ating machinery, may be impaired for some time after use of propofol. Propofol induced impairment is not generally detectable beyond 12 hours (please see section 4.4).

4.8 Undesirable effects

Induction and maintenance of anaesthesia or sedation with propofol is generally smooth with minimal evidence of excitation. The most commonly reported ADR are pharmacologically predictable side effects of an anaesthetic/sedative agent, such as hypotension. The nature, severity and incidence of adverse events observed in patients receiving propofol may be related to the condition of the recipients and the operative or therapeutic procedures being undertaken.

Table of Adverse Drug Reactions

⁽¹⁾ Serious bradycardias are rare. There have been isolated reports of progression to asystole.

⁽²⁾ Occasionally, hypotension may require use of intravenous fluids and reduction of the administration rate of propofol.

⁽³⁾ Very rare reports of rhabdomyolysis have been received where propofol has been given at doses greater than 4 mg/kg/hr for ICU sedation.

⁽⁴⁾ May be minimised by using the larger veins of the forearm and antecubital fossa. With Propofol-Lipuro 0.5 % (5 mg/ml) local pain can also be minimised by the co-administration of lidocaine.

⁽⁵⁾ Combinations of these events, reported as “Propofol infusion syndrome”, may be seen in seriously ill patients who often have multiple risk factors for the develop-ment of the events, see section 4.4.

⁽⁶⁾ Brugada-type ECG - elevated ST-segment and coved T-wave in ECG. ⁽⁷⁾ Rapidly progressive cardiac failure (in some cases with fatal outcome) in adults. The cardiac failure in such cases was usually unresponsive to inotropic supportive treatment.

⁽⁸⁾ Abuse of and drug dependence on propofol, predominantly by health care profes-sionals.

⁽⁹⁾ Not known as it cannot be estimated from the available clinical trial data. ⁽¹⁰⁾ Necrosis has been reported where tissue viability has been impaired. Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via

United Kingdom

• the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

Ireland

HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2

Tel: +353 1 6764971; Fax: +353 1 6762517.

Website: www.hpra.ie; e-mail: medsafety@hpra.ie

4.9 Overdose

Accidental overdose is likely to cause cardiorespiratory depression. Respiratory depres-sion should be treated by artificial ventilation with oxygen. Cardiovascular depression may require lowering the patient’s head and, if severe, use of plasma expanders and pressor agents.

1. 5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmaco-therapeutic group: other general anaesthetics, ATC-code N01AX10.

Mechanism of action, pharmacodynamic effect

After intravenous injection of Propofol-Lipuro 0.5 % (5 mg/ml), onset of the hypnotic effect occurs rapidly. Depending on the rate of injection, the time to induction of an-aesthesia is between 30 and 40 seconds. The duration of action after a single bolus administration is short due to the rapid metabolism and excretion (4 – 6 minutes). With the recommended dosage schedule, a clinically relevant accumulation of propofol after repeated bolus injection has not been observed.

Patients recover consciousness rapidly.

Bradycardia and hypotension occasionally occur during induction of anaesthesia prob-ably due to a lack of vagolytic activity. The cardio-circulatory situation usually normal-ises during maintenance of anaesthesia.

The rationale for developement of Propofol-Lipuro 0.5 % (5 mg/ml) was the reduction of pain at injection site; this was clearly demonstrated in two clinical studies, one in children and one in adults.

The formulation of propofol in a mixed medium- and long-chain triglyceride emul-sion leads to lower concentrations of free propofol in the aqueous phase compared to pure long-chain triglyceride emulsions. This difference may explain the reduced pain frequency and intensity observed with Propofol-Lipuro formulations in comparative clinical studies, especially with Propofol-Lipuro 0.5 % (5 mg/ml) due to the very low concentration of free propofol.

Paediatric population

Limited studies on the duration of propofol based anaesthesia in children indicate safety and efficacy is unchanged up to duration of 4 hours. Literature evidence of use in children documents use for prolonged procedures without changes in safety or efficacy.

5.2 Pharmacokinetic properties

Distribution

After intravenous administration about 98 % of propofol is bound to plasma protein. After intravenous bolus administration the initial blood level of propofol declines rap-idly due to rapid distribution into different compartments (a-phase). The distribution half-life has been calculated as 2 – 4 minutes.

During elimination the decline of blood levels is slower. The elimination half-life dur-ing the b-phase is in the range of 30 to 60 minutes. Subsequently a third deep com-partment becomes apparent, representing the re-distribution of propofol from weakly perfused tissue.

The central volume of distribution is in the range of 0.2 – 0.79 l/kg body weight, the steady-state volume of distribution in the range of 1.8 – 5.3 l/kg body weight. Biotransformation

Propofol is mainly metabolized in the liver to form glucuronides of propofol and glu-curonides and sulphate conjugates of its corresponding quinol. All metabolites are inactive.

Elimination

Propofol is rapidly cleared from the body (total clearance approx. 2 l/min). Clearance occurs by metabolism, mainly in the liver, where it is blood flow dependent. Clearance is higher in children compared with adults. About 88 % of an administered dose is excreted in the form of metabolites in urine. Only 0.3 % is excreted unchanged in urine. Paediatric population

After a single dose of 3 mg/kg intravenously, propofol clearance/kg body weight in-creased with age as follows: Median clearance was considerably lower in neonates < 1 month old (n = 25) (20 ml/kg/min) compared to older children (n = 36, age range 4 months – 7 years). Additionally inter-individual variability was considerable in neo-nates (range 3.7 – 78 ml/kg/min). Due to this limited trial data that indicates a large variability, no dose recommendations can be given for this age group. Median propofol clearance in older aged children after a single 3 mg/kg bolus was 37.5 ml/min/kg (4 – 24 months) (n=8), 38.7 ml/min/kg (11 – 43 months) (n=6), 48 ml/min/ kg (1 – 3 years)(n = 12), 28.2 ml/min/kg (4 – 7 years)(n = 10) as compared with 23.6 ml/min/kg in adults (n=6).

5.3 Preclinical safety data

Preclinical data reveal no specific hazard for humans based on conventional stud-ies on repeated dose toxicity or genotoxicity. Carcinogenicity studies have not been conducted.

Published studies in animals (including primates) at doses resulting in light to moder-ate anaesthesia demonstrate that the use of anaesthetic agents during the period of rapid brain growth or synaptogenesis results in cell loss in the developing brain that can be associated with prolonged cognitive deficiencies. The clinical significance of these nonclinical findings is not known..

Teratogenic effects have not been observed.

In local tolerance studies, intramuscular injection resulted in tissue damage around the injection site.

1. 6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Soya-bean oil refined,

medium-chain triglycerides,

glycerol,

egg lecithin,

sodium oleate,

water for injections.

6.2 Incompatibilities

This medicinal product must not be mixed with other products except those mentioned in section section 6.6.

6.3 Shelf life

2 years.

After first opening: to be used immediately.

After dilution according to directions: administration of dilutions must commence immediately after preparation.

6.4 Special precautions for storage

Do not store above 25 °C.

Do not freeze.

6.5 Nature and contents of container

This medicinal product is supplied in glass ampoules of 20 ml

Glass ampoules are made of colourless glass (type I) according to Pharm. Eur.. Pack sizes:

Glass ampoules: 5 x 20 ml

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in accordance with local requirements.

Containers should be shaken before use.

For single use in one patient only. Any portion of contents remaining after use must be discarded. If two layers can be seen after shaking the product should not be used. Propofol-Lipuro 0.5 % (5 mg/ml) should only be mixed with the following products: glucose 50 mg/ml (5 % w/v) solution, sodium chloride 9 mg/ml (0.9 % w/v) solution and preservative-free lidocaine injection 10 mg/ml (1 %) (refer to section 4.2, subsec-tion “Infusion of diluted Propofol-Lipuro 0.5 % (5 mg/ml)”)

Co-administration of Propofol-Lipuro 0.5 % (5 mg/ml) together with glucose 50 mg/ml (5% w/v) solution or sodium chloride 9 mg/ml (0.9 % w/v) solution via a Y-connector close to the injection site is possible.

1. 7. MARKETING AUTHORISATION HOLDER

B. Braun Melsungen AG

Carl-Braun-Straße 1 Postal address:

34212 Melsungen, Germany 34209 Melsungen, Germany Phone: +49/5661/71-0

Fax: +49/5661/71-4567

1. 8. MARKETING AUTHORISATION NUMBER

PA0736/018/004 (Ireland)

PL 03551/0113 (United Kingdom)

1. 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:

21^st July 2008 (Ireland)

05/06/2013 (United Kingdom)

Date of last renewal: 5^th June 2013 (Ireland)

1. 10. DATE OF REVISION OF THE TEXT

October 2018

Method of administration

You will receive Propofol-Lipuro 0.5 % (5 mg/ml) by intravenous injection or infusion, that is, through a needle or small tube placed in one of your veins. Your circulation and breathing will be constantly monitored while you are being given the injection or the infusion.

If you received more Propofol-Lipuro 0.5 % (5 mg/ml) than you should

It is unlikely that this occurs because the doses you receive are very carefully controlled. Yet if you accidentally got an overdose, this could lead to depression of heart function and breathing. In this case your doctor will employ any necessary treatment immedi-ately.

If you have any further questions on the use of this product, ask your doctor or phar-macist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

A doctor must be called immediately if the following happen Common (may affect up to 1 in 10 people):

• Low blood pressure that might occasionally need infusion of fluids and reduction of the speed of administration of propofol.
• Too low heartbeat that might be serious in rare cases.

Rare (may affect up to 1 in 1,000 people):

• Convulsions like in epilepsy

Very rare: (may affect up to 1 in 10,000 people)

• Allergic reactions including swelling of the face, tongue or throat, wheezing breath, skin redness and low blood pressure
• There have been cases of unconsciousness occurring after operations. You will there-fore be carefully observed during the waking-up time.
• Water on the lungs (lung oedema) after administration of propofol
• Inflammation of the pancreas

Not known (frequency cannot be estimated from the available data):

• There have been reports of isolated cases of severe adverse reactions presenting as a combination of the following symptoms: breakdown of muscle tissue, accumulation of acidic (sour) substances in the blood, abnormally high blood potassium level, high blood fat levels, abnormalities in the electrocardiogram (Brugada-type ECG), liver enlargement, irregular heart-beat, kidney failure and heart failure. This has been called the “propofol infusion syndrome”. Some of the affected patients eventually died. These effects have only been seen in patients in intensive care with doses higher than 4 mg of propofol per kg body weight per hour. See also section 2, ‘Warn-ings and precautions’.

Other side effects are:

Very common (affects more than 1 treated patient of 10):

• Pain at the injection site occurring during the first injection. The pain may be re-duced by injecting propofol into larger veins of the forearm. Injection of lidocaine (a local anaesthetic) and propofol at the same time also helps to reduce the pain at the injection site.

Common (may affect up to 1 in 10 people):

• Short interruption of breathing
• Headache during the time of recovery
• Sickness or vomiting during the time of recovery

Uncommon (may affect up to 1 in 100 people):

• Blood clots in veins or inflammation of veins at the injection site Very rare (may affect up to 1 in 10,000 people)
• Loss of sexual control during the time of recovery
• Abnormal colour of urine after longer lasting administration of propofol
• Cases of fever after an operation

• Tissue damage after the medicine was accidentally injected outside of a vein

  Not known (frequency cannot be estimated from the available data):

  • Involuntary movements
  • Abnormally good mood
  • Drug abuse and drug dependence
  • Failure of the heart
  • Shallow breathing
  • Pain and/or swelling at the injection site after the medicine was accidentally injected outside of a vein
  • Breakdown of muscle tissue has been reported very rarely in cases where propofol has been given at greater doses than recommended for sedation in intensive care units

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below). By reporting side effects you can help provide more information on the safety of this medicine.

United Kingdom:

• to the Medicines and Healthcare Products Regulatory Agency via the yellow card scheme:

www.mhra.gov.uk/yellowcard

Ireland:

HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2;

Tel: +353 1 6764971; Fax: +353 1 6762517.

Website: www.hpra.ie; e-mail: medsafety@hpra.ie

5. How to store Propofol-Lipuro 0.5 % (5 mg/ml)

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label and the carton after EXP. The expiry date refers to the last day of that month. Do not store above 25°C. Do not freeze.

Propofol-Lipuro 0.5 % (5 mg/ml) must be used immediately after opening/dilution. Do not use Propofol-Lipuro 0.5 % (5 mg/ml) if two separate layers can be seen after shaking the ampoule.

Do not throw away any medicines via wastewater or household waste. Ask your phar-macist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Propofol-Lipuro 0.5 % (5 mg/ml) contains

• The active substance is propofol.

  Each millilitre of Propofol-Lipuro 0.5 % (5 mg/ml) contains 5 mg of propofol. 1 ampoule of 20 ml contains 100 mg propofol.

• The other ingredients are:

  Soya-bean oil, refined,

  Medium-chain triglycerides,

  Egg lecithin,

  Glycerol,

  Sodium oleate,

  Water for injections.

What Propofol-Lipuro 0.5 % (5 mg/ml) looks like and contents of the pack

It is an emulsion for injection or infusion.

It is a milky-white oil-in water emulsion.

It comes in glass ampoules of 20 millilitres, available in packs of 5 ampoules. Marketing Authorisation Holder and Manufacturer

B. Braun Melsungen AG

Carl-Braun-Straße 1 Postal address:

34212 Melsungen, Germany 34209 Melsungen, Germany

Phone: +49/5661/71-0 Fax: +49/5661/71-4567

This medicinal product is authorised in the Member States of the EEA under the following names:

Propofol-Lipuro 0.5% (5 mg/ml): Czech Republic, Spain, Ireland, Portugal,

Slovakia, United Kingdom Propofol-Lipuro 5 mg/ml: Italy

Propofol “B.Braun” 5 mg/ml: Denmark

Propofol-Lipuro 5 mg/ml: Finland, France, Hungary, Norway, Poland,

Sweden

Propofol-Lipuro 5 mg/ml

Emulsion zur Injektion oder Infusion: Austria, Germany, Luxembourg This leaflet was last revised in September 2018.

The following information is intended for healthcare professionals only:

The containers are for single use in one patient only.

Any unused emulsion must be thrown away at the end of administration. The containers must be shaken before use.

For complete information on this medicinal product please refer to the summary of product characteristics.

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